Efficacy of non-pharmacological interventions for individuals with amyotrophic lateral sclerosis: systematic review and network meta-analysis of randomized control trials

This network meta-analysis (NMA) aimed to compare the efficacy of five non-pharmacological interventions, including exercise intervention (EI), nutritional intervention (NI), respiratory intervention (RI), psychological intervention (PSI), and integrated physical intervention (IPI), on functional status, quality of life, muscle strength, pulmonary function, and safety in patients with amyotrophic lateral sclerosis (ALS). We searched nine databases, PubMed, Cochrane, Embase, Scopus, Web of Science, CNKI, CBM, WFPD, and CSTJ, for randomized controlled trials of ALS patients. The primary outcome was the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were the McGill Quality of Life Questionnaire (McGill-QoL), Medical Research Council (MRC)-sum score, Forced Vital Capacity (FVC), and Fatigue Severity Scale (FSS) score. This NMA was conducted using random-effect models to calculate the standard mean difference (SMD) and 95% confidence interval (CI). All types of supplemental interventions had some benefit for patients with ALS. EI had a beneficial effect on the ALSFRS-R score (SMD: 1.01; 95% CI 0.50–1.51), FVC (SMD: 0.78; 95% CI 0.02–1.55), McGill-QoL (SMD: 0.71 95% CI 0.33–1.08), and MRC (SMD: 1.11; 95% CI 0.08–2.14). RI had a beneficial effect on the ALSFRS-R score (SMD: 0.83 95% CI 0.12–1.55). IPI had a beneficial effect on the ALSFRS-R score (SMD: 0.65 95% CI 0.06–1.24). NI had a beneficial effect on the McGill-QoL (SMD: 0.63 95% CI 0.02–1.23). The current study findings support a multimodal intervention strategy with an emphasis on EI for slowing disease progression in patients with ALS.


Search strategies
Two independent researchers searched nine databases: PubMed, Cochrane, Embase, Scopus, Web of Science, CNKI, CBM, WFPD, and CSTJ, from inception to June 2023.We conducted the online search for the articles published between the periods using the following logic: (1) "amyotrophic lateral sclerosis" or "ALS"; (2) "respiratory treatment," "psychology treatment," "respiratory treatment," "psychology treatment," "physiotherapy," "nutritional treatment," and "exercise treatment"; and (3) "randomized controlled trial" or "RCT" or "randomized" or "placebo." The search strategy was developed first for the PubMed database and then adapted for the other sources.Experts in ALS and intervention then reviewed these sources to make sure they were complete and accurate.The detailed search strategy is presented in Supplementary Appendix 1.

Study selection
The Endnote 21 software was used to select eligible articles, exclude duplicates, and filter out articles that did not meet the inclusion criteria.Two researchers independently read the titles and abstracts, initially selected potential studies, screened the full texts, and chose the studies that ultimately met the requirements.A third investigator resolved any discrepancies, if necessary.Finally, eligible studies were documented and recorded using a PRISMA flow chart.

Data extraction
Two independent investigators extracted the data.A third investigator was called in to help resolve data discrepancies and provide a consensus for decision-making.The data were then recorded by author and year, number of participants (male and female ratio), age, treatments, and outcome index.

Risk-of-bias assessment
The Cochrane risk-of-bias assessment tool (Review Manager 5.4) was used to evaluate selection bias, implementation bias, measurement bias, follow-up bias, reporting bias, and other potential biases.The quality of studies was graded by two evaluators and classified as "low, high, or unclear risk of bias." If a disagreement arose, a third evaluator stepped in to resolve the issue.The risk of bias is presented in Supplementary Appendix 2.

Statistical analyses
NMA was performed using STATA 14.0 MP software to incorporate an indirect comparison of non-pharmacological interventions for ALS.Because the data in this NMA are all continuous variables with different scales for www.nature.com/scientificreports/ each outcome indicator, the standard mean difference (SMD) and 95% confidence interval (CI) were calculated.A p-value ≤ 0.05 was considered statistically significant for between-group differences.Consistency and inconsistency tests between studies were used to improve study stability.A funnel plot was used to detect publication bias.The effectiveness of the interventions was ranked using the surface under the cumulative ranking curve (SUCRA) and mean rank, which considers all possible rankings and uncertainties in intervention effects; a greater SUCRA value indicated a more effective intervention.

Literature search and study inclusion
As shown in Fig. 1, the initial research on the nine databases yielded 3,968 studies.After 835 duplicates were removed, the first round of screening resulted in the selection of 537 studies based on the titles and abstracts.After reading the full articles, 62 studies were chosen.Thirty-seven of these were subsequently excluded due to an incompatible outcome index (n = 16) or not being an RCT (n = 21).The remaining 25 eligible studies were included in the NMA.

Quality assessment
The randomization methods used in the 25 RCTs were random sequence generation (n = 14), random number table method (n = 3), computer-generated randomization lists (n = 3), permuted block randomization (n = 4), and duplo-cego randomization (n = 1).Except for EI and PSI, allocation concealment was used to prevent selection bias in all remaining RCTs.For participant and personnel blinding, 11 studies used double blinding, two studies used single blinding, and the remaining studies did not specify.For detection bias, eight studies were assessor-blinded, while the remaining studies did not report.One study had a selective bias.Our study was free of attrition and other biases.Overall, the quality assessment of the included studies was high.

Small sample effect
Publication bias is a critical factor in determining the validity and generalization of conclusions in systemic reviews and meta-analyses.In this meta-analysis, a funnel plot was used to detect publication bias, with effect  www.nature.com/scientificreports/size on the horizontal coordinate and standard error on the vertical coordinate.As the sample size increases and the standard error decreases, trials are likely to converge around the true underlying effect size.The funnel plots of the trials used in the current study indicate a lower likelihood of publication bias in the ALSFRS-R score (Fig. 2a), FVC (Fig. 2b), McGill-QoL (Fig. 2c), MRC (Fig. 2d), and FSS score (Fig. 2e).

Consistency and inconsistency analysis
An inconsistency analysis of our network meta-analysis indicates a stable model with no significant evidence of discrepancy in indirect comparisons.The restricted maximum likelihood method was used in conjunction with a www.nature.com/scientificreports/variance-covariance matrix proportional to 0.5I (3) + 0.5 J (3,3,1).Furthermore, the specific test for inconsistency within the model yielded a chi-square value and probability value, which are shown in Supplementary Appendix 3, supporting our conclusion that the observed data do not deviate significantly from what would be expected under a consistent model.This analysis provides strong evidence to support the consistency assumption in our network meta-analysis.4a depicts a forest plot of the ALSFRS-R score.Compared to Con, the effect on functional capacity was greater in EI (SMD = 1.01, 95% CI 0.50 ~ 1.51), RI (SMD = 0.83, 95% CI 0.12 ~ 1.55), IPI (SMD = 0.65, 95% CI 0.06 ~ 1.24), NI (SMD = 0.47, 95 CI − 0.11 ~ 1.04), and PSI (SMD = 0.33, 95 CI − 0.90 ~ 1.55).Taken together, the primary outcomes of the NMA indicate that EI is the most effective strategy for slowing the functional capacity decline due to ALS.

Discussion
This study examined the efficacy of five interventions on functional status, pulmonary function, muscle strength, quality of life, and the severity of fatigue by performing a systematic review and network meta-analysis of 25 RCTs involving 1,226 ALS patients.To the best of our knowledge, this is the first study to show that, despite intervention-specific benefits, EI outperformed RI, IPI, NI, and PSI on all metrics except severity of fatigue.In agreement with the current study findings, the beneficial effect of EI on the functional status of ALS patients has been reported in many previous studies.For example, unsupervised structured home exercise or progressive muscle training combined with aerobic exercise resulted in improved functional status in terms of the ALSFRS-R score, Functional Independence Measure (FIM), and Barthel scores, as well as improved quality of life in ALS patients [20][21][22] .The beneficial effects of EI are also reported in animal studies.For instance, swimming training modifies muscle metabolism by increasing muscle bioenergetics and decreasing oxidative stress.This training also slows grip strength loss and increases lifespan in the G93A-SOD1 mouse, which expresses a G93A mutant form of human copper-zinc superoxide dismutase 1 (SOD1) and can be used for ALS research 23 .There are some explanations for the suppressive effects of EI on disease progression in ALS patients.First, exercise training activates satellite cells that reside between the basal lamina and sarcolemma of adult skeletal myofibers.These cells aid in muscle repair and regeneration in ALS patients.Second, exercise training increases the production of neuroprotective hormones 24,25 .Resistance training and aerobic exercise, for example, have been shown to increase growth hormone secretion [26][27][28][29][30] , which promotes growth hormone (GH) binding to intracellular receptors on the cell membrane and stimulates target cell proliferation 31 .
Because respiratory failure is unavoidable and a leading cause of death in ALS patients, RI has become a focal point for the disease.For example, ALS rodent models lose a lot of intercostal motor neurons and phrenic neurons.This makes the respiratory system much harder to use by placing more metabolic stress on the remaining neurons 32,33 .This type of unfavorable compensatory mechanism hastens motor neuron death 34 .In contrast, RI has been shown to improve brain-derived neurotrophic factor (BDNF)-dependent synthesis of phrenic neuronal output rates, which improves ALS patients' quality of life, ability to perform actions, and ability to breathe 35,36 .One systematic review demonstrated that RI improves respiratory muscle function with an effect size of 1.48 and a 12-month mean survival extension 37 .
IPI has also demonstrated unique therapeutic benefits on the ALSFRS-R scale score.Scalp acupuncture, which is widely used in research and clinical settings for neurodegenerative diseases, has shown promise as a treatment for ALS.For example, eight-week acupuncture therapy helped a 55-year-old female ALS patient by improving dorsiflexion strength and easing cramps, fasciculations, and lower limb pain 38 .Four-week acupuncture injection point therapy improved speech clarity, motor function, and muscle strength in two ALS patients 39 .Additionally, massage has been shown to help relieve clinical symptoms of ALS, such as muscle stiffness and cramping, by activating the parasympathetic nervous system through force on the skin surface and exerting pressure on the muscles to increase blood flow 40 .
Because oxidative stress is an important hypothesis for ALS pathogenesis, antioxidant research has become popular 41 .Vitamins, particularly vitamin B12 and vitamin E, play a protective role in the development of ALS 42 .Creatine monohydrate administration has a positive trend in the survival of ALS patients with no adverse events 43 .Malnutrition and weight loss are common in ALS patients 44,45 .High-calorie and ultra-high-calorie supplements can play an important role in increasing the body weight of ALS patients 46 .
PSI may help ALS patients with depression and improve their quality of life.For example, hypnosis and mindfulness-based psychological interventions improved patients' quality of life and relieved their pain, depression, and anxiety while also slowing disease progression 47,48 .Physiologically, PSI has been shown to increase telomere length and activity in leukocytes, promote telomeric DNA synthesis, and counteract the telomere depletion seen in the pathology of ALS [49][50][51] , while suppressing oxidative stress through increased levels of ROSdegrading enzymes 52 .
Fatigue is a common symptom seen at all stages of ALS pathology and is associated with worse functioning, poor quality of life, increased pain intensity and disease severity, and muscle weakness.Female ALS patients are more often affected by fatigue 53 .None of the non-pharmacological interventions included in the current study have shown a clear improvement in the FSS score compared to CON.
Even though it outperforms other interventions, selecting or recommending EI with the highest SUCRA ranking should not be a routine procedure for patients with ASL due to the following reasons.First, the efficacy of EI may vary depending on the stage of ALS 54,55 , potentially leading to bias in interpreting the intervention's results.That is, patients in the early stages of ALS are more likely to maintain the physical ability required for participation in such interventions, excluding those in later stages, for whom exercise may be impractical or, at the very least, significantly more difficult.Second, the potential bias in exercise modalities and durations adds another layer of complexity 16,56 , implying that the therapeutic benefits observed in this study may not be uniformly attributable to exercise itself, but rather to its specific characteristics, such as intensity, frequency, and patients' physical condition at the start of the intervention.This nuance highlights the possibility of varying response rates across the ALS population, complicating the task of generalizing our findings to the larger ALS community.To address these concerns, future research should take a more stratified methodological approach, ensuring that participants are not only representative of the broader ALS spectrum, but also categorized according to disease stage, physical capacity, and intervention specifics.Such stratification would enable a more granular analysis of the data, facilitating a nuanced understanding of the relationship between exercise interventions and ALS progression.Taken together, there may be insufficient evidence to draw a firm conclusion about the superior efficacy of EI for ALS patients, raising the risk of misinterpreting the efficacy hierarchy of the interventions in slowing the disease progression.
This meta-analysis included RCTs with varying degrees of blinding, ranging from double-blind to studies with unspecified blinding procedures  . We inluded studies regardless of blinding statutes due to a scarcity of ALS intervention research and methodological considerations.As a result, heterogeneity in blinding may introduce bias, compromising the internal validity of the results.Blinding, particularly double blinding, is the gold standard for RCTs, but its practical application in ALS trials presents significant challenges.They include the difficulty of masking certain interventions, ethical concerns about placebo control for life-altering conditions, and the possibility of unblinding due to the intervention's obvious effects 57,59,61 .Transparency in reporting the blinding process, including successes and failures, will allow for a more nuanced interpretation of trial results.It is critical to understand that developing blinding methods in ALS trials is a methodological and ethical requirement for ensuring the credibility of research findings and maintaining patient care integrity 82,83 .
Finally, the ALSFRS-R is a validated tool for tracking the progression of disability in the bulbar, motor, and respiratory domains in ALS 84 .Thus, individual subscale scores of the ALRFRS-R rather than total scores may provide more useful information about the progression of disability in ALS 85,86 , as the effects of the interventions included in the current study may be domain-specific.However, due to limited access to original datasets, our study relied on a total score rather than individual subscale scores.As a result, the therapeutic effects of the www.nature.com/scientificreports/interventions on ALSFRS-R scores observed in the current study should be interpreted with caution and more specific in terms of bulbar, motor, and respiratory domains.This represents a limitation in our analysis framework and necessitates a thorough discussion.As a result, it is critical to recognize that, while the ALSFRS-R is a useful tool for tracking disease progression and patient function, using a total score rather than individual subscale scores may introduce bias when assessing the effectiveness of specific interventions that it directly queries.By contrast, a recent study found that the ALSFRS-R bulbar subscale had poor to fair screening accuracy for detecting global pharyngeal dysphagia, while the ALSFRS-R swallowing item had poor overall screening accuracy for both global swallowing and safety status 87 .As a result, future research could benefit from using metrics that assess respiratory function independently of the ALSFRS-R.This results in a more accurate representation of the efficacy of interventions, lowering bias risks and increasing the clinical relevance of the findings.

Conclusions
To the best of our knowledge, we are the first to compare the effectiveness of the five non-pharmacologic interventions for ALS patients.We conducted a systematic review and NMA of 25 RCTs with a total of 1226 patients and showed that EI is more effective than the other interventions, but some benefits are unique to each intervention.The current study findings support a multimodal intervention strategy with an emphasis on EI for slowing disease progression in patients with ALS.At the same time, it is also critical to interpret these findings with the knowledge that the stage of disease may influence the feasibility and effectiveness of these interventions.Further research is required to determine the full scope of these interventions' applicability and to optimize intervention strategies for diverse patient profiles across the ALS spectrum.

Figure 2 .
Figure 2. Funnel plot.ALSFRS-R Amyotrophic lateral sclerosis Functional Rating Scale-Revised, FVC Forced Vital Capacity, McGill-QoL McGill Quality of Life Questionnaire, MRC Medical Research Council, FSS Fatigue Severity Scale.

FigureFigure 3 .
Figure 3a depicts the network diagram of eligible comparisons for the primary outcome of the ALSFRS-R scores.Figure 3b-e show the network diagrams of eligible comparisons for the secondary outcomes of FVC, McGill-QoL,

Figure 4 .
Figure 4. Forest Plot for eligible comparisons for all interventions included in the analysis.ALSFRS-R Amyotrophic lateral sclerosis Functional Rating Scale-Revised, FVC Forced Vital Capacity, McGill-QoL McGill Quality of Life Questionnaire, MRC Medical Research Council, FSS Fatigue Severity Scale. https://doi.org/10.1038/s41598-024-62213-w

Table 1
summarizes the 25 RCTs that included 1226 patients eligible for data analysis.The studies included four respiratory interventions, two psychological interventions, six physiotherapy interventions, six nutritional interventions, and seven exercise interventions conducted between 1996 and 2022 and were published in English.

Table 1 .
Characteristics of studies used for analysis.RI respiratory intervention, PSI psychological intervention, PHI physiotherapy intervention, NI nutritional intervention, EI exercise intervention, ALSFRS-R Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, FVC Forced Vital Capacity, ALSSQOL-R Amyotrophic Lateral Sclerosis-Specific Quality of Life, MMT Manual Muscle Testing, SF-36 Short Form (36), FSS Fatigue Severity scale, McGill-QoL McGill Quality of Life Questionnaire, MRC Medical Research Council, VAS fatigue Visual Analog Scale for Fatigue, NA Not Available.

Table 2 .
SUCRA rankings from six-node analysis.ALSFRS-R Amyotrophic lateral sclerosis Functional Rating Scale-Revised, FVC Forced Vital Capacity, McGill-QoL McGill Quality of life Questionnaire, MRC Medical Research Council, FSS Fatigue Severity Scale, SUCRA surface under the cumulative ranking curve.